My proposal addresses the following question: can hyperacute rejection (HAR) of xenografts be altered if recipient species-specific complement inhibitors are expressed in donor endothelium? To answer this question, this proposal involves the study of three systems of increasing complexity. The first and least complex system will involve lining a prosthetic vascular graft with porcine endothelial cells transfected with and expressing human complement inhibitors. A more complicated second system will involve transfecting endothelial cells of a segment of porcine artery with human complement inhibitors. The third experimental approach will involve transfection of recipient complement inhibitors into pig heart endothelium. In the three systems, the xenograft will be perfused with human blood as a source of complement and other mediators of HAR in an ex vivo perfusion circuit currently employed in the sponsors' laboratory. The degree of cellular damage and evidence of HAR will be evaluated extensively.